ABSTRACT The Developmental Therapeutics Program (DTP) is significantly restructured from the former Structural and Chemical Biology and Experimental Therapeutics Programs creating a new program with 39 primary and 24 secondary members from 13 departments within the Schools of Medicine and Engineering, and Duke University. Members have expertise within the drug development continuum, from solving structures of new targets, to generation of chemically diverse libraries, to hit to lead optimization, and discovery of new technologies to improve drug delivery. Several members discovered new cancer therapies that have been advanced into the clinic and even through to FDA approval. The program is organized around three research focus groups that all share a common goal of building within the DCI a capability to take cutting edge targets such as oncogenic drivers, and define novel therapeutics in the form of small molecules or biologics. First, the cancer-related activities of the structural and chemical biology group has been strengthened by its reassignment to Developmental Therapeutics and increased interaction/collaboration with experts in cancer drug development. Structures of attractive cancer targets have been solved by program members who have forged intra-programmatic collaborations to rationally create diverse chemical libraries based on insight into structure-activity-relationships. Second, over the past five years the molecular targets and therapeutics group has benefitted from new members with expertise in designing diverse chemical libraries and development of new high throughput screening platforms. An intra- and inter-programmatic, multi-investigator collaboration focused on the development of a new theranostic application for small molecule inhibitors was awarded the only DOD Breast Cancer Research Program (BCRP) Transformative Vision Award ($19 million/5 year) out of 80 applications reviewed in 2012. DTP has also benefitted from newly recruited members with novel high throughput screening technologies that have been used to discover new chemical entities targeting developmental pathways critical to cancer cell growth/survival, and a new target for an approved anti- helminthic drug, the latter finding currently being transitioned into the clinic through an inter-programmatic collaboration with the Solid Tumor Therapeutics Program. In addition, members of the program were awarded the only Clinical Translational Research Award funded in 2012, an intra- and inter-programmatic multi- investigator award funded through the DOD BCRP to develop HER3 vaccines for breast cancer indications. In this regard, at least eight immunotherapeutics (tumor vaccines) developed through the research of program members have entered clinical trials conducted in collaboration with investigators in the Solid Tumor Therapeutics and Brain Tumor Programs. Third, members of the drug delivery focus group have developed proprietary technologies to improve solubility and tumor delivery of chemotherapeutic drugs, including targeted kinase inhibitors. Value added by the Duke Cancer Institute (DCI) to the research activities of DTP members includes: (i) DCI subsidized shared resources, which are heavily utilized by program members; (ii) the DCI supported tissue repository; (iii) a human tumor explant facility that is DCI supported; and (iv) the creation of an umbrella cancer research (basic/translational/clinical) organization that has fostered research collaborations. Program members are supported by $19.4 million of peer-reviewed cancer-related funding, $1.8 million of which is from the NCI. Primary program members published 807 manuscripts during the funding period, 4% of which were intra-programmatic collaborations and 31% of which were inter-programmatic.